Malignant Peripheral Nerve Sheath Tumors (MPNST) affect between 5-13% of Neurofibromatosis type 1 (NF1) patients and is a leading cause of mortality in this disease. We are using tumor cell lines from both mouse and human MPNSTs to test drugs for growth inhibition. We are focusing on late phase and FDA approved drugs, primarily from the Cancer Therapy Evaluations Program (CTEP), in the tyrosine kinase inhibitor family and comparing the results to doxorubicin, one of the standard treatment options for MPNST. We are studying the changes in transcriptome and kinome caused by these drugs for rational design of synergistic combinations. Candidate combinations will be tested first in tumor cell lines in culture and then in MPNST xenograft and genetically engineered mouse models. Because all the drugs we're testing have been through phase I clinical testing, we are comparing inhibitory effects at the Cmax found in patient serum at the maximum tolerated dose in humans. Successful synergistic combinations will be considered for clinical trials in MPNST patients.